PURPOSETo determine the following: (1) the feasibility of combining the antiretroviral didanosine (ddl) with a 96-hour continuous intravenous (IV) infusion of cyclophosphamide (800 mg/m2), doxorubicin (50 mg/m2), and etoposide (240 mg/m2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection; (2) the effect of ddl on CDE-induced myelosuppression and CD4 lymphopenia; and (3) the effect of CDE on serum p24 antigen and quantitative HIV blood cultures.METHODSTwenty-five patients with HIV-related NHL received CDE every 28 or more days. Consecutive patients were assigned in an alternating fashion to group A (ddl given at a standard dose during cycles one, two, five, and six) or group B (ddl given during cycles three, four, five, and six).RESULTSddl use was associated with less leukopenia (mean nadir, 3.33 v 1.49 x 10(3)/microL; p = .03), neutropenia (2.38 v 1.07 x 10(3)/microL; p = .03), and thrombocytopenia (76 v 48 x 10(3)/microL; p = ...

Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma.

Despite the established impact of highly active antiretroviral therapy (HAART) in reducing HIV-related morbidity and mortality, malignancy remains an important cause of death. Patients who receive the combination of cancer chemotherapy and HAART may achieve better response rates and higher rates of survival than patients who receive antineoplastic therapy alone. However, the likelihood of drug interactions with combined therapy is high, since protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are substrates and potent inhibitors or inducers of the cytochrome P450 (CYP) system. Since many antineoplastic drugs are also metabolised by the CYP system, coadministration with HAART could result in either drug accumulation and possible toxicity, or decreased efficacy of one or both classes of drugs. Although formal, prospective pharmacokinetic interaction studies are not available in most instances, it is possible to infer the nature of drug interactions based on the metabolic fates of these agents. Paclitaxel and docetaxel are both metabolised by the CYP system, although differences exist in the nature of the isoenzymes involved. Case reports describing adverse consequences of concomitant taxane-antiretroviral therapy exist. Although other confounding factors may have been present, these cases serve as reminders of the vigilant monitoring necessary when taxanes and HAART are coadministered. Similarly, vinca alkaloids are substrates of CYP3A4 and are, thus, vulnerable to PI- or NNRTI-mediated changes in their pharmacokinetics. Interactions with the alkylating agents cyclophosphamide and ifosfamide are complicated as a result of the involvement of the CYP3A4 and CYP2B6 isoenzymes in both the metabolic activation of these drugs and the generation of potentially neurotoxic metabolites. Existing data regarding the metabolic fate of the anthracyclines doxorubicin and daunorubicin suggest that clinically detrimental interactions would not be expected with coadministered HAART. Commonly used endocrine therapies are largely substrates of the CYP system and may, therefore, be amenable to modulation by concomitant HAART. In addition, tamoxifen itself has been associated with reduced concentrations of both anastrozole and letrozole, raising the concern that similar inducing properties may adversely affect the outcome of PI- or NNRTI-based therapy. Similarly, dexamethasone is both a substrate and concentration-dependent inducer of CYP3A4; enhanced corticosteroid pharmacodynamics may result with CYP3A4 inhibitors, while the efficacy of concomitant HAART may be compromised with prolonged dexamethasone coadministration. Since PIs and NNRTIs may also induce or inhibit the expression of P-glycoprotein, the potential for additional interactions to arise via modulation of this transporter also exists. Further research delineating the combined safety and pharmacokinetics of antiretrovirals and antineoplastic therapy is necessary.

Interactions between antiretrovirals and antineoplastic drug therapy.

Treatment of HIV-infected patients with highly active antiretroviral therapy (HAART) has altered the natural history of human immunodeficiency virus (HIV) infection by decreasing the frequency of opportunistic infections and altering the expected frequency of hematologic complications and AIDS-related malignancies. Thrombotic thrombocytopenic purpura and thrombosis resulting from protein S deficiency are relatively rare complications of HIV in the United States in patients taking HAART, but are frequent in the developing world where these drugs are not available. Cytopenia, particularly anemia, are more common and result both from bone marrow failure and peripheral destruction. Hodgkin's and non-Hodgkin's lymphoma are still problematic in patients with advanced disease with high viral loads. This review will examine and discuss the diagnosis and management of the hematologic complications of HIV.

Hematologic complications of HIV infection

Optimizing treatment of HIV-associated lymphoma.

Clinical aspects and management of AIDS-related lymphoma.

Based on our prior data suggesting a therapeutic advantage for infusional administration of cyclophosphamide (C), doxorubicin (D), and etoposide (E) in patients with relapsed and resistant non-Hodgkin's lymphoma (NHL), we administered C (750 mg/m2), D (50 mg/m2), and E (240 mg/m2) via continuous intravenous infusion over 96 hours as first line therapy for 21 patients with intermediate- or high-grade non-Hodgkin's lymphoma associated with human immunodeficiency virus (HIV) infection. Treatment was repeated every 28 or more days. The median CD4 count of the study group was 87/ul, and the median serum lactate dehydrogenase was 383 IU/L. Extranodal disease, lymphomatous marrow involvement, and lymphomatous meningitis were present at diagnosis in 90%, 33%, and 10% of patients, respectively. Complete response (CR) occurred in 13 patients (62%, 95% confidence intervals 41%, 81%) and partial response occurred in five patients (24%). The estimated median survival of the study group was 18.0 months. Hematologic toxicity required dose reduction for 47% of cycles and for 79% of patients who received at least two cycles. The mean dose intensity for C, D, and E were 73%, 70%, and 73% of the intended dose intensity, respectively. Opportunistic infection included oral/esophageal candidiasis (N = 7), herpes labialis (N = 3), pulmonary Mycobacterium avium-intracellulare (N = 1), candidemia (N = 1), pneumonitis (N = 1), and disseminated aspergillosis than resulted in a single treatment-related death (5%). Treatment resulted in a significant decrease in the CD4+ lymphocytes, as well as total lymphocytes, T lymphocytes, and CD8+ lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Infusional cyclophosphamide, doxorubicin and etoposide in HIV-related non-Hodgkin's lymphoma: a follow-up report of a highly active regimen.

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Infusional cyclophosphamide, doxorubicin and etoposide in HIV-related non-Hodgkin's lymphoma: a follow-up report of a highly active regimen.